1. Everolimus, an mTORC1/2 inhibitor, in ART-suppressed individuals who received solid organ transplantation: A prospective study
- Author
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Erica A. Gibson, Peter G. Stock, Jeffrey M. Milush, Francesca T. Aweeka, Timothy J. Henrich, Louise E. Hogan, Cassandra Thanh, Simon Chu, Brian Richardson, Teri Liegler, Steven G. Deeks, Rodney Rogers, Corinna Schreiner, Michael P. Busch, Cheryl M. Cameron, Sonia Bakkour, Amelia N. Deitchman, Rachel L. Rutishauser, Christopher C. Baker, and Arya Zarinsefat
- Subjects
Oncology ,Adult ,medicine.medical_specialty ,translational research/science ,infectious disease ,Clinical Trials and Supportive Activities ,mTORC1 ,immunosuppression/immune modulation ,030230 surgery ,Mechanistic Target of Rapamycin Complex 1 ,clinical research/practice ,Medical and Health Sciences ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Clinical Research ,Internal medicine ,Gene expression ,human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome [infection and infectious agents - viral] ,Genetics ,Immunology and Allergy ,Medicine ,Gene silencing ,Humans ,Pharmacology (medical) ,organ transplantation in general ,Prospective Studies ,Everolimus ,Prospective cohort study ,PI3K/AKT/mTOR pathway ,Transplantation ,business.industry ,Evaluation of treatments and therapeutic interventions ,Organ Transplantation ,everolimus [immunosuppressant - mechanistic target of rapamycin] ,Infectious Diseases ,Pharmaceutical Preparations ,6.1 Pharmaceuticals ,HIV/AIDS ,Surgery ,business ,Infection ,Immunosuppressive Agents ,medicine.drug ,Biotechnology - Abstract
Pharmacologic inhibition of the mammalian target of rapamycin (mTOR) in the setting of renal transplantation has previously been associated with lower human immunodeficiency virus 1 (HIV-1) DNA burden, and in vitro studies suggest that mTOR inhibition may lead to HIV transcriptional silencing. Because prospective clinical trials are lacking, we conducted an open-label, single-arm study to determine the impact of the broad mTOR inhibitor, everolimus, on residual HIV burden, transcriptional gene expression profiles, and immune responses in HIV-infected adult solid organ transplant (SOT) recipients on antiretroviral therapy. Whereas everolimus therapy did not have an overall effect on cell-associated HIV-1 DNA and RNA levels in the entire cohort, participants who maintained everolimus time-averaged trough levels >5ng/mL during the first 2months of therapy had significantly lower RNA levels up to 6months after the cessation of study drug. Time-averaged everolimus trough levels significantly correlated with greater inhibition of mTOR gene pathway transcriptional activity. Everolimus treatment also led to decreased PD-1 expression on certain T cell subsets. These data support the rationale for further study of the effects of mTOR inhibition on HIV transcriptional silencing in non-SOT populations, either alone or in combination with other strategies. Trial Registration: ClinicalTrials.gov NCT02429869.
- Published
- 2021